U.S. patent number 4,344,945 [Application Number 06/241,727] was granted by the patent office on 1982-08-17 for piperidine derivatives.
This patent grant is currently assigned to Kyowa Hakko Kogyo Co., Ltd.. Invention is credited to Yutaka Kasuya, Kazuhiro Kubo, Hiroyuki Obase, Haruki Takai, Masayuki Teranishi.
United States Patent |
4,344,945 |
Teranishi , et al. |
August 17, 1982 |
Piperidine derivatives
Abstract
New piperidine derivatives which have a useful pharmacological
activity such as hypotensive activity are prepared.
Inventors: |
Teranishi; Masayuki (Machida,
JP), Obase; Hiroyuki (Machida, JP), Takai;
Haruki (Kawasaki, JP), Kubo; Kazuhiro (Berchem,
BE), Kasuya; Yutaka (Komukainishi, JP) |
Assignee: |
Kyowa Hakko Kogyo Co., Ltd.
(Tokyo, JP)
|
Family
ID: |
26367266 |
Appl.
No.: |
06/241,727 |
Filed: |
March 9, 1981 |
Foreign Application Priority Data
|
|
|
|
|
Mar 10, 1980 [JP] |
|
|
55-29106 |
May 27, 1980 [JP] |
|
|
55-69619 |
|
Current U.S.
Class: |
514/229.8;
514/222.8; 514/230.5; 544/11; 544/92; 544/95 |
Current CPC
Class: |
C07D
211/58 (20130101) |
Current International
Class: |
C07D
211/00 (20060101); C07D 211/58 (20060101); C07D
413/04 (); A61K 031/445 (); A61K 031/535 (); C07D
498/14 () |
Field of
Search: |
;544/92,95
;424/248.52,248.53,248.54,248.55,248.57 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Primary Examiner: Ford; John M.
Attorney, Agent or Firm: Craig and Antonelli
Claims
What is claimed is:
1. A compound represented by the formula: ##STR115## wherein A is
hydroxy, halogen, lower alkyl, lower alkoxy, lower alkenyloxy,
lower alkinyloxy, lower alkylthio, carboxy, lower alkoxycarbonyl,
nitro, amino, lower alkylamino, lower alkanoylamino, sulfamoyl,
mono- or di-lower alkylaminosulfonyl, lower alkylsulfonyl,
carbamoyl, cyano or trifluoromethyl, m is 0 or an integer of 1-5,
and when m is 2 or more, each A is the same group or each A is a
different group or two A groups may combine to form lower
alkylenedioxy; X is oxygen, sulfur, carbonyl, hydroxymethylene or
methylene; R.sub.1 is straight-chain alkylene having 1-4 carbon
atoms with or without lower alkyl substituent(s); R.sub.2 is
hydrogen or lower alkyl; and R.sub.3 is hydroxy, lower alkoxy,
halogen, trifluoromethyl, trifluoromethoxy, trifluoromethylthio,
nitro or amino, n is 0 or an integer of 1-4, and when n is 2 or
more, each R.sub.3 is the same group or each R.sub.3 is a different
group of two R.sub.3 groups may combine to form lower alkylenedioxy
and a pharmacologically acceptable acid addition salt thereof.
2. A compound represented by the formula: ##STR116## wherein
A.sub.1, A.sub.2 and A.sub.3 each represent the same group or a
different group, and A.sub.1, A.sub.2 and A.sub.3 each are
hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy, lower
alkenyloxy, lower alkinyloxy, lower alkylthio, carboxy, lower
alkoxycarbonyl, nitro, amino, lower alkylamino, lower
alkanoylamino, sulfamoyl, mono- or di-lower alkylaminosulfonyl,
lower alkylsulfonyl, carbamoyl, cyano or trifluoromethyl, and
A.sub.1 and A.sub.2 or A.sub.2 and A.sub.3 may combine to form a
lower alkylenedioxy, and X is oxygen, sulfur, carbonyl,
hydroxymethylene or methylene; R.sub.1 is straight-chain alkylene
having 1-4 carbon atoms with or without lower alkyl substituent(s);
and a pharmacologically acceptable acid addition salt thereof.
3. A compound according to claim 2, wherein at least one of
A.sub.1, A.sub.2 and A.sub.3 is lower alkoxy or halogen, or A.sub.1
and A.sub.2 or A.sub.2 and A.sub.3 combine to form lower
alkylenedioxy.
4. A compound according to claim 2, wherein X is carbonyl or
hydroxymethylene.
5. A compound according to claim 2, wherein R.sub.1 is methylene
with or without lower alkyl substituent(s).
6. A compound according to claim 1 or 2 wherein said
pharmacologically acceptable acid addition salt thereof is selected
from the group consisting of hydrochloride, hydrobromide,
hydroiodide, nitrate, sulfate, phosphate, acetate, benzoate,
maleate, fumarate, succinate, tartrate, citrate, oxalate,
glyoxylate, aspartate, methanesulfonate, ethanesulfonate,
propanesulfonate, methanedisulfonate,
.alpha.,.beta.-ethanedisulfonate and benzenesulfonate.
7. A hypotensive composition which comprises at least one
pharmaceutically acceptable carrier, and an effective amount of a
compound represented by the formula: ##STR117## wherein A is
hydroxy, halogen, lower alkyl, lower alkoxy, lower alkenyloxy,
lower alkinyloxy, lower alkylthio, carboxy, lower alkoxycarbonyl,
nitro, amino, lower alkylamino, lower alkanoylamino, sulfamoyl,
mono- or di-lower alkylaminosulfonyl, lower alkylsulfonyl,
carbamoyl, cyano or trifluoromethyl, m is 0 or an integer of 1-5,
and when m is 2 or more, each A is the same group or each A is a
different group or two A groups may combine to form lower
alkylenedioxy; X is oxygen, sulfur, carbonyl, hydroxymethylene or
methylene; R.sub.1 is straight-chain alkylene having 1-4 carbon
atoms with or without lower alkyl substituent(s); R.sub.2 is
hydrogen or lower alkyl; and R.sub.3 is hydroxy, lower alkoxy,
halogen, trifluoromethyl, trifluoromethoxy, trifluoromethylthio,
nitro or amino, n is 0 or an integer of 1-4, and when n is 2 or
more, each R.sub.3 is the same group or each R.sub.3 is a different
group or two R.sub.3 groups may combine to form lower alkylenedioxy
or a pharmacologically acceptable acid addition salt thereof.
Description
The present invention relates to novel piperidine derivatives, acid
addition salts thereof and pharmaceutical compositions containing
the same.
The piperidine derivatives are compounds represented by the formula
[I]: ##STR1## wherein A is hydroxy, halogen, lower alkyl, lower
alkoxy, lower alkenyloxy, lower alkynyloxy, lower alkylthio,
carboxy, lower alkoxycarbonyl, nitro, amino, lower alkylamino,
lower alkanoylamino, sulfamoyl, mono- or di-lower
alkylaminosulfonyl, lower alkylsulfonyl, carbamoyl, cyano or
trifluoromethyl, m is 0 or an integer of 1-5, and when m is 2 or
more, each A is the same group or each A is a different group or
two A groups may combine to form lower alkylenedioxy; X is oxygen,
sulfur, carbonyl, hydroxymethylene or methylene; R.sub.1 is
straight-chain alkylene having 1-4 carbon atoms with or without
lower alkyl substitutent(s); R.sub.2 is hydrogen or lower alkyl; p
and q are 0 or 1 provided that p and q are not both 0 or 1 at the
same time, B is ##STR2## and when p is 1 and q is 0, B is ##STR3##
and when q is 1 and p is 0, B is ##STR4## and R.sub.3 is hydroxy,
lower alkoxy, halogen, trifluoromethyl, trifluoromethoxy,
trifluoromethylthio, nitro or amino, n is 0 or an integer of 1-4,
and when n is 2 or more, each R.sub.3 is the same group or each
R.sub.3 is a different group, or two R.sub.3 groups may combine to
form lower alkylenedioxy.
The compounds represented by the formula [I] and the
pharmaceutically acceptable acid addition salts thereof have a
hypotensive activity, and therefore are useful as medicine.
Heretofore, the following compounds, each having a piperidine ring,
are commercially available as tranquilizers. ##STR5##
Further, Japanese Published Patent Application No. 160371/1979 and
WO 80/00024 published on Jan. 10, 1980 disclose piperidine
derivatives having a hypotensive activity. Representative ones of
the piperidine derivatives are represented by the following
formula: ##STR6## wherein Aa is methoxy or two Aa groups may
combine to form methylenedioxy; s is 0 or an integer of 1-3; (Xa is
carbonyl, hydroxymethylene or methylene; and Ra is hydrogen or
methyl). A. U.S. application based on the PCT application is
pending (U.S. patent application Ser. No. 191,339 filed on Jan. 31,
1980).
Further, piperidine derivatives having a hypotensive activity are
disclosed in U.S. patent application Ser. No. 209,284 filed on Nov.
21, 1980.
Some of the inventors of the above applications are common with the
present invention.
Compounds having excellent pharmacological activities are always in
demand. In order to obtain such compounds, studies have been made
on piperidine derivatives and as a result, it has been found that
novel piperidine derivatives represented by the formula [I] have a
hypotensive activity. Further, it has been found that some
compounds in the compounds represented by the formula [I] have an
antiulcer activity, an antiplatelet aggregation activity, a
cholesterol-lowering activity, antihistaminic activity or trachea
relaxant activity.
The present invention relates to the compounds represented by the
above formula [I] (hereinafter referred to as Compound [I] and
terms like this shall apply to other compounds), acid addition
salts thereof and their use as medicine.
Halogen in the definition of A and R.sub.3 in Compound [I] includes
chlorine, bromine, etc. The term "lower" in the definition of the
various groups in Compound [I] means having 1-5 carbon atoms,
especially 1-3, except for "lower alkoxycarbonyl" which has 2-6
carbon atoms, especially 2-4.
Compound [I] includes all of the optical isomers.
Examples of pharmacologically acceptable acid addition salts of
Compound [I] are inorganic acid addition salts such as
hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate and
phosphate, and organic acid addition salts such as acetate,
benzoate, maleate, fumarate, succinate, tartrate, citrate, oxalate,
glyoxylate, aspartate, methanesulfonate, ethanesulfonate,
propanesulfonate, methanedisulfonate,
.alpha.,.beta.-ethanedisulfonate and benzenesulfonate.
Especially preferable compounds with the formula representing
Compound [I] are represented by the formula [I']: ##STR7## wherein
A.sub.1, A.sub.2 and A.sub.3 each are the same group or each are a
different group, and A.sub.1, A.sub.2 and A.sub.3 are hydrogen or
have the same definition as that of the above-mentioned A group in
Formula [I]; and X, R.sub.1, p, q and B have the same meaning or
definition as described in Formula [I].
Examples of Compound [I] are tabulated in the following Table 1.
Table 2 shows structures and Tables 3-1, 2 and 3 show properties of
the present compounds.
TABLE 1 ______________________________________ Compound No.
Compound ______________________________________ 1
1-(3,4-dimethyoxybenzoylmethyl)-4-(2-oxo-3,4-
dihydro-2H-1,3-benzoxazin-3-yl)piperidine 2
1-(3,4-methylenedioxybenzoylmethyl)-4-(2-oxo-
3,4-dihydro-2H-1,3-benzoxazin-3-yl)piperidine 3
1-[2-(3,4-dimethoxyphenyl)-2-hydroxyethyl]-4-
(2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl) piperidine 4
1-[2-(3,4-methylenedioxyphenyl)-2-hydroxyethyl]-
4-(2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl) piperidine 5
1-[1-(3,4-dimethoxybenzoyl)-ethyl]-4-(2-oxo-3,4-
dihydro-2H-1,3-benzoxazin-3-yl)piperidine 6
1-[3-(3,4-dimethoxyphenyl)-3-hydroxypropan-2-yl]-
4-(2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl) piperidine 7
1-(3,4,5-trimethoxybenzoylmethyl)-4-(2-oxo-3,4-
dihydro-2H-1,3-benzoxazin-3-yl)piperidine 8
1-[2-(3,4,5-trimethoxyphenyl)-2-hydroxyethyl]-
4-(2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl) piperidine 9
1-(3,4-dimethoxybenzoylmethyl)-4-(3,4-dihydro-
2,2-dioxo-1H-2,1,3-benzothiadiazin-3-yl) piperidine 10
1-[2-(3,4-dimethoxyphenyl)-2-hydroxyethyl]-4-
(3,4-dihydro-2,2-dioxo-1H-2,1,3-benzothiadiazin- 3-yl)piperidine 11
1-(3,4-methylenedioxybenzoylmethyl)-4-(3,4-
dihydro-2,2-dioxo-1H-2,1,3-benzothiadiazin-3- yl)piperidine 12
1-[2-(3,4-methylenedioxyphenyl)-2-hydroxyethyl]-
4-(3,4-dihydro-2,2-dioxo-1H-2,1,3-benzothiadiazin- 3-yl)piperidine
13 1-(3,4-dimethoxybenzoylmethyl)-4-(3,4-dihydro-
2,2-dioxo-1H-2,1,3-benzothiadiazin-1-yl) piperidine 14
1-(3,4-methylenedioxybenzoylmethyl)-4-(3,4-
dihydro-2,2-dioxo-1H-2,1,3-benzothiadiazin-1-yl) piperidine 15
1-[2-(3,4-dimethoxyphenyl)-2-hydroxyethyl]-4-
(3,4-dihydro-2,2-dioxo-1H-2,1,3-benzothiadiazin- 1-yl)piperidine 16
1-[2-(3,4-methylenedioxyphenyl)-2-hydroxyethyl]-
4-(3,4-dihydro-2,2-dioxo-1H-2,1,3-benzothiadiazin- 1-yl)piperidine
17 1-[1-(3,4-dimethoxybenzoyl)ethyl]-4-(3,4-dihydro-
2,2-dioxo-1H-2,1,3-benzothiadiazin-1-yl)piperidine 18
1-[3-(3,4-dimethoxyphenyl)-3-hydroxypropan-2-yl]-
4-(3,4-dihydro-2,2-dioxo-1H-2,1,3-benzothiadiazin- 1-yl)piperidine
______________________________________
TABLE 2
__________________________________________________________________________
Structure of compound ##STR8## Com- pound Structure No. A.sub.1
A.sub.2 A.sub.3 X R.sub.1 B p q
__________________________________________________________________________
##STR9## ##STR10## H ##STR11## CH.sub.2 ##STR12## 1 0 2 ##STR13## H
##STR14## CH.sub.2 ##STR15## 1 0 3 ##STR16## ##STR17## H ##STR18##
CH.sub.2 ##STR19## 1 0 4 ##STR20## H ##STR21## CH.sub.2 ##STR22## 1
0 5 ##STR23## ##STR24## H ##STR25## ##STR26## ##STR27## 1 0 6
##STR28## ##STR29## H ##STR30## ##STR31## ##STR32## 1 0 7 ##STR33##
##STR34## ##STR35## ##STR36## CH.sub.2 ##STR37## 1 0 8 ##STR38##
##STR39## ##STR40## ##STR41## CH.sub.2 ##STR42## 1 0 9 ##STR43##
##STR44## H ##STR45## CH.sub.2 ##STR46## 1 0 10 ##STR47## ##STR48##
H ##STR49## CH.sub.2 ##STR50## 1 0 11 ##STR51## H ##STR52##
CH.sub.2 ##STR53## 1 0 12 ##STR54## H ##STR55## CH.sub.2 ##STR56##
1 0 13 ##STR57## ##STR58## H ##STR59## CH.sub.2 ##STR60## 0 1 14
##STR61## H ##STR62## CH.sub.2 ##STR63## 0 1 15 ##STR64## ##STR65##
H ##STR66## CH.sub.2 ##STR67## 0 1 16 ##STR68## H ##STR69##
CH.sub.2 ##STR70## 0 1 17 ##STR71## ##STR72## H ##STR73## ##STR74##
##STR75## 0 1 18 ##STR76## ##STR77## H ##STR78## ##STR79##
##STR80## 0 1
__________________________________________________________________________
TABLE 3
Properties (Melting point: IR, NMR and Elementary analysis)
(1) The term "form" means the state of a compound subjected to the
determination of properties.
Blank: free base
EtOH: ethanol of crystallization
HCl: hydrochloride
(2) The values in the column of infrared absorption spectrum (IR)
show characteristic maximum absorption of the compounds measured in
KBr tablet.
(3) The values in the table of nuclear magnetic resonance spectrum
(NMR) and .delta. values based on TMS in CDCl.sub.3
(Compound Nos. 1-10, 13 and 15), d.sub.6 -dimethylsulfoxide
(d.sub.6 -DMSO)
(Compound Nos. 11, 12, 14 and 16) or CD.sub.3 OD+D.sub.2 O
(Compound Nos. 17 and 18)
(4) Elementary analysis
A: Calculated
F: Found
TABLE 3-1 ______________________________________ Compound No. Form
m.p. (.degree.C.) IR (cm.sup.-1)
______________________________________ 1 143.0-144.5 1680, 1715
1735 2 163.0-164.0 1680, 1710 1720(sh) 3 169.0-170.0 1715 4
185.7-186.2 1715 5 149.0-151.5 1715, 1720(sh) 1680 6 201.0-202.0
1700 7 152.0-153.5 1690, 1720 8 203.0-204.0 1705 9 173.5-175.5
1670, 1345, 1170 10 171.0-172.5 1350, 1340, 1170 11 184.0-185.5
1680, 1342, 1170 12 178.0-179.0 1350, 1340, 1170 13 3/2 EtOH
102.0-104.0 1680, 1350, 1340, 1170 14 185.0-187.0 1685, 1335, 1165
15 144.5-146.0 1350, 1340, 1180 16 194.5-195.0 1345, 1175 17
HCl.EtOH 229.0-231.5 1660, 1348, 1332, 1160 18 HCl 221.0-222.0
1350(sh), 1342, 1165 ______________________________________
TABLE 3-2 ______________________________________ Com- pound No.
Form NMR (ppm) ______________________________________ 1 1.5-2.6,
2.9-3.4, 3.80, 3.93, 4.40, 6.8-7.8 2 1.6-2.6, 2.9-3.4, 3.73, 4.37,
6.03, 6.73-7.70 3 1.6-3.50, 2.50(d), 3.83, 3.86, 4.36, 4.13-4.83,
6.70-7.46 4 1.6-4.1, 4.1-4.83, 4.40, 5.93, 6.60-7.50 5 1.30(d),
1.50-3.30, 3.96, 4.35, 3.70-4.60, 6.80-7.90 6 0.78(d), 1.60-3.30,
3.86, 3.90, 4.41, 3.60-4.60, 6.66-7.46 7 1.30-2.63, 2.83-3.36,
3.86, 3.93, 4.40, 4.1-4.6, 6.9-7.5 8 1.50-3.60, 2.53(d), 3.83,
3.86, 4.40, 4.06-4.86, 6.60, 6.80-7.46 9 1.50-2.50, 2.80-3.30,
3.75, 3.90, 3.93, 4.67, 6.20-7.75 10 1.43-2.0, 2.10-3.33,
3.50-4.10, 3.86, 4.36-5.20, 4.70, 6.50-7.36 11 1.30-3.10,
3.20-3.90, 3.67, 4.66, 6.10, 6.6-7.7 12 1.30-2.43, 2.66-3.13,
3.20-3.76, 4.36- 4.80, 5.93, 6.56-7.30 13 3/2 EtOH 1.53-2.60,
2.76-3.40, 3.75, 3.90, 3.93, 4.46, 5.13(broad), 6.73-7.73 14
1.53-2.40, 2.70-3.40, 3.53-4.13, 3.73, 4.36, 6.12, 6.90-7.76 15
1.70-3.33, 3.81, 3.85, 3.90-4.76, 4.41, 6.63-7.50 16 1.46-2.60,
2.76-3.46, 3.60-4.13, 4.20- 5.10, 4.40, 5.96, 6.60-7.80 17 HCl.EtOH
1.50(d), 2.10-2.80, 3.06-3.70, 3.96, 4.0, 4.56, 5.28(quartet),
7.10-7.93 18 HCl 1.25(d), 2.12-2.75, 3.05-4.18, 3.89, 4.56,
5.43(broad), 6.92-7.47 ______________________________________
TABLE 3-3 ______________________________________ A: Calculated, F:
Found Compound Rational Elementary analysis (%) No. formula C H N
______________________________________ 1 C.sub.23 H.sub.26 N.sub.2
O.sub.5 A 67.30 6.39 6.82 F 67.11 6.51 6.64 2 C.sub.22 H.sub.22
N.sub.2 O.sub.5 A 66.99 5.62 7.10 F 67.05 5.59 6.96 3 C.sub.23
H.sub.28 N.sub.2 O.sub.5 A 66.97 6.84 6.79 F 66.97 6.87 6.77 4
C.sub.22 H.sub.24 N.sub.2 O.sub.5 A 66.65 6.10 7.07 F 66.61 6.01
7.04 5 C.sub.24 H.sub.28 N.sub.2 O.sub.5 A 67.91 6.65 6.60 F 67.73
6.76 6.40 6 C.sub.24 H.sub.30 N.sub.2 O.sub.5 A 67.59 7.09 6.57 F
67.67 7.27 6.52 7 C.sub.24 H.sub.28 N.sub.2 O.sub.6 A 65.44 6.41
6.36 F 65.62 6.51 6.23 8 C.sub.24 H.sub.30 N.sub.2 O.sub.6 A 65.14
6.83 6.33 F 65.30 7.00 6.26 9 C.sub.22 H.sub.27 N.sub.3 O.sub.5 S A
59.31 6.11 9.43 F 59.45 6.14 9.17 10 C.sub.22 H.sub.29 N.sub.3
O.sub.5 S A 59.04 5.53 9.39 F 59.31 6.63 9.09 11 C.sub.21 H.sub.23
N.sub.3 O.sub.5 S A 58.59 5.62 9.76 F 58.87 5.38 9.49 12 C.sub.21
H.sub.25 N.sub.3 O.sub.5 S A 58.32 6.06 9.72 F 58.58 5.94 9.57 13
C.sub.22 H.sub.27 N.sub.3 O.sub.5 S. A 58.35 7.05 8.16 3/2EtOH F
58.61 6.83 8.12 14 C.sub.21 H.sub.23 N.sub.3 O.sub.5 S A 58.59 5.62
9.76 F 58.81 5.39 9.58 15 C.sub.22 H.sub.29 N.sub.3 O.sub.5 S A
59.04 6.53 9.39 F 59.31 6.58 9.31 16 C.sub.21 H.sub.25 N.sub.3
O.sub.5 S A 58.32 6.06 9.72 F 58.08 5.86 9.33 17 C.sub.23 H.sub.29
N.sub.3 O.sub.5 S. A 55.39 6.69 7.75 HCl.EtOH F 55.19 6.57 8.05 18
C.sub.23 H.sub.31 N.sub.3 O.sub.5 S. A 55.47 6.48 8.44 HCl F 55.50
6.70 8.18 ______________________________________
Hypotensive activity and acute toxicity of Compound [I] are
illustrated below as experiments.
Experiment 1
This experiment is conducted according to the method described in
"Spontaneously Hypertensive Rats (SHR) Guidelines for Breeding,
Care and Use" (published by SHR Conference) (1976) p. 11.
Five spontaneously hypertensive rats (15 weeks old, 180 mmHg or
more in blood pressure) are used as one group. Each of the test
compound is added to 0.3% (w/v) CMC aqueous solution in a
concentration of 3 mg/ml. Each of the mixtures is orally
administered to the rats in a dose of 1 ml/100 g. Changes in blood
pressure are measured according to the method of tail artery
plethysmography (see the literature cited above). The maximum
reduction (mmHg) in blood pressure after the administration on the
basis of the pressure immediately before the administration is
shown in Table 4.
TABLE 4 ______________________________________ Maximum Maximum
reduction reduction Compound in blood pressure Compound in blood
pressure No. (mmHg) No. (mmHg)
______________________________________ 1 40*.sup.2 10 15 2 3 11 17
3 25*.sup.1 12 27 4 30*.sup.1 45*.sup.2 13 22 5 3 14 30 6 17 15 30
7 13 16 18 8 12 17 17 9 25 18 10
______________________________________ *.sup.1 25 mg/kg
administration *.sup.2 50 mg/kg administration
Experiment 2
The compound of Compound No. 16 is used as a test compound. Three
male dd-strain mice (weight 20.+-.1 g) are used for the test
compound.
The compound is added to aqueous physiological sodium chloride, and
the mixture is orally (P.O.) administered to the mice in a dose of
1000 mg/kg. After the observation for 7 days, the number of deaths
is counted. The result is that no death is observed.
Now, the process for preparing Compound [I] is described below.
Compound [I] may be prepared by reacting a compound represented by
the formula [II]: ##STR81## (wherein, R.sub.2, p, q, B, R.sub.3 and
n have the same definitions as defined above) or Compound [II]
wherein R.sub.3 is protected, with a compound represented by the
formula [III] ##STR82## (wherein A, m and R.sub.1 have the same
definitions as defined above; X' is oxygen, sulfur, carbonyl or
methylene; and Z is halogen or an eliminable group) or Compound
[III] wherein A is protected, and further if necessary, by reducing
the resulting product and if necessary, by eliminating the
protective group therefrom.
In the definition of Z, halogen includes chlorine, bromine or
iodine; and the eliminable group includes alkylsulfonyloxy (for
example, methanesulfonyloxy), arylsulfonyloxy (for example,
benzenesulfonyloxy or p-toluenesulfonyloxy), etc.
The reaction of Compound [II] or the protected one with Compound
[III] or the protected one is carried out in an inert solvent.
Ketone (e.g. acetone), halogenated hydrocarbon (e.g. chloroform and
methylene chloride), amide (e.g. dimethylformamide), sulfoxide
(e.g. dimethylsulfoxide), substituted or unsubstituted aromatic
hydrocarbon (e.g. benzene, toluene and chlorobenzene), lower
alcohol (e.g. methanol, ethanol and isopropanol), etc. may be used
alone or in combination as an inert solvent. The reaction is
carried out at 0.degree.-150.degree. C., preferably at a
temperature between room temperature and the boiling point of the
solvent depending on the reactivity of the group Z which is
exchangeable. The reaction usually proceeds very smoothly in the
presence of a base such as lower alcoholate (e.g. sodium methylate
and sodium ethylate), alkali hydroxide (e.g. sodium hydroxide),
alkali carbonate (e.g. sodium carbonate and potassium carbonate),
tertiary amine (e.g. triethylamine and pyridine), etc. The amount
of the base is usually 1.0 to 1.2 times the equivalent amount based
on Compound [II]. When an acid addition salt of Compound [II] such
as hydrochloride is used, it goes without saying that the base
supplementary enough to neutralize the acid is added thereto. Use
of reaction-promoting agents such as potassium iodide is effective
for smooth proceeding of the reaction.
When either R.sub.3 or A, or both is(are) hydroxy, amino or lower
alkylamino, these groups are protected in a conventional manner
prior to the above reaction. After completion of the reaction, the
protective group is eliminated in a conventional manner to obtain
the desired product.
When X' is carbonyl, the resulting product is reduced to obtain
Compound [I] wherein X is hydroxymethylene. The reaction may be
carried out by reacting Compound [I] wherein X is carbonyl with a
complex metal hydride such as sodium borohydride in a lower alcohol
such as methanol, ethanol and isopropanol at -10.degree. to
100.degree. C., preferably at a temperature between 0.degree. C.
and the boiling point of the used solvent. Alternatively, the
reaction may be carried out by subjecting Compound [I] wherein X is
carbonyl to catalytic reduction using hydrogenating catalyst such
as palladium carbon, Raney nickel, platinum black, platinum carbon
and platinum oxide in lower alcohol such as methanol and ethanol,
lower aliphatic acid such as acetic acid, water or a mixed solvent
thereof. These reactions may be carried out either in an open
vessel or in a closed vessel under pressure. When the carbon atom
of R.sub.1 adjacent to X is an asymmetrical carbon in the above
reduction, Compound [I] is stereo-selectively obtained according to
the reduction method. That is, Compound [I] in threo form is
obtained when a complex metal hydride is used and Compound [I] in
erythro form is obtained according to catalytic reduction in an
acidic condition. The acidic condition is brought with inorganic
acids such as hydrochloric acid or organic acids such as acetic
acid, propionic acid and succinic acid.
Compound [II] used as a starting compound of Compound [I] is also a
new compound. Compound [II] is classified as described in Table 5
for convenience.
TABLE 5
__________________________________________________________________________
Compound p q B No. Formula
__________________________________________________________________________
1 0 ##STR83## II-1 ##STR84## 1 0 ##STR85## II-2 ##STR86## 0 1
##STR87## II-3 ##STR88##
__________________________________________________________________________
Compound [II-1] is produced as shown below. First, an
4-amino-piperidine derivative represented by the formula [IV]:
##STR89## (wherein, R.sub.2 has the same definitions as defined
above and R.sub.4 is a protective group for an amino group) is
reacted with a salicylaldehyde or a derivative thereof represented
by the formula [V]: ##STR90## (wherein, R.sub.3 and n have the same
definitions as defined above) to prepare a compound represented by
the formula [VI]: ##STR91## (wherein, R.sub.2, R.sub.3, R.sub.4 and
n have the same meaning as defined above).
Examples of the substituents R.sub.4 in the Compound [IV] are acyl
(e.g. acetyl and benzoyl), alkyloxycarbonyl (e.g.
tert.-butoxycarbonyl and ethoxycarbonyl), benzyl, tosyl and mesyl.
The reaction can be carried out either without any solvent or in a
lower alkanol (e.g. methanol, ethanol and propanol), an aromatic
hydrocarbon (e.g. benzene, toluene and xylene), a halogenated
hydrocarbon (e.g. methylene chloride and chloroform) or a mixture
thereof.
The reaction in an alkanol has the advantage that the conversion to
a compound represented by the formula [VII] below can be carried
out without isolation of Compound [VI] from the reaction solution.
As regards the amounts of the reactants to be used, it is proper to
use Compound [V] in an amount of 1.0 to 1.2 equivalent weights,
preferably 1.0 equivalent weight, of Compound [IV]. Although the
reaction proceeds at room temperature in a short time, it may be
carried out at an elevated temperature, if necessary.
Then, Compound [VI] is reduced with a complex metal hydride (e.g.
sodium borohydride and sodium cyanoborohydride) in a lower alkanol
(e.g. methanol, ethanol and isopropanol) to prepare a compound
represented by the formula [VII]: ##STR92## (wherein, R.sub.2,
R.sub.3, R.sub.4 and n have the same meaning as defined above).
This reaction is advantageously carried out at -10.degree. to
100.degree. C., preferably 0.degree. C. to room temperature.
Subsequently, Compound [VII] is reacted with a carbonic acid
derivative such as phosgene, trichloromethyl chloroformate, alkyl
chlorocarbonate, 1,1'-carbonyldiimidazole and urea to prepare a
compound represented by the formula [VIII]: ##STR93## (wherein,
R.sub.2, R.sub.3, R.sub.4 and n have the same meaning as defined
above).
All of the above reactions can be carried out according to
conventional methods and the reaction wherein
1,1'-carbonyldiimidazole is used is particularly described
hereinafter. The reaction is carried out in an aprotic polar
solvent such as halogenated hydrocarbon (e.g. methylene chloride
and chloroform), ether (e.g. ethyl ether, tetrahydrofuran and
dioxane), acetonitrile, dimethylformamide and dimethylsulfoxide, in
combination thereof or alone, preferably with stirring. Preferably,
the amount of 1,1'-carbonyldiimidazole is 1.0 to 2.0 times the
equivalent amount based on Compound [VII]. The reaction is carried
out at a temperature of from room temperature to the boiling point
of the used solvent. The reaction is usually completed in 1 to 3
hours when treated at the boiling point of the solvent and is
completed in 10 to 15 hours, when treated at room temperature.
Finally, Compound [VIII] is converted to Compound [II-1] by being
subjected to the usual reaction for eliminating the
amino-protecting group. The reaction when the amino-protecting
group is benzyl is particularly described below. The
benzyl-eliminating reaction is carried out by subjecting Compound
[VIII] to catalytic reduction in the presence of palladium (e.g.
palladium carbon) in a lower alcohol (e.g. methanol, ethanol and
isopropanol), water or a mixed solvent thereof. The reaction is
preferably carried out in the presence of a mineral acid (e.g.
hydrochloric acid, hydrobromic acid, hydroiodic acid and perchloric
acid). The proper amount of the mineral acid is 1 to 2 times the
equivalent amount based on Compound [VIII]. Proper reaction
temperature is room temperature to 50.degree. C.
Compound [II-2] is produced as shown below. First, a compound
represented by the formula [IX]: ##STR94## (wherein, R.sub.2 and
R.sub.4 have the same meaning as defined above) is reacted with a
compound represented by the formula [X]: ##STR95## (wherein,
R.sub.3 and n have the same meaning as defined above) to prepare a
compound represented by the formula [XI]: ##STR96## (wherein,
R.sub.2, R.sub.3, R.sub.4 and n have the same meaning as defined
above).
This reaction can be carried out in the same manner as that in the
preparation of Compound [VI] from Compounds [IV] and [V].
Then, Compound [XI] is reduced to prepare a compound represented by
the formula [XII]: ##STR97## (wherein, R.sub.2, R.sub.3, R.sub.4
and n have the same significance as defined above).
This reaction can be carried out in the same manner as that in the
preparation of Compound [VII] from Compound [VI].
Then, Compound [XII] is further reduced to prepare a compound
represented by the formula [XIII]: ##STR98## (wherein, R.sub.2,
R.sub.3, R.sub.4 and n have the same meaning as defined above).
This reaction can be performed by the methods generally adopted for
the purpose of reducing a nitro group into an amino group, for
example, the method involving combined use of a metal such as Sn,
Fe or Zn and a mineral acid such as hydrochloric acid and sulfuric
acid or an organic acid such as acetic acid, the method resorting
to use of a sulfide or hydrazine and the catalytic reduction in the
presence of a catalyst such as palladium carbon. When the reduction
is performed by the catalytic method, the reaction is effected by
causing the Compound [XII] to absorb an equivalent weight of
hydrogen in water, a lower alkanol such as methanol and ethanol, or
a mixture thereof. The reaction is preferably carried out from
20.degree. C. to 60.degree. C., especially around room
temperature.
Compound [XIII] is reacted with sulfurylamide (H.sub.2 NSO.sub.2
NH.sub.2) to prepare a compound represented by the formula [XIV]:
##STR99## (wherein, R.sub.2, R.sub.3, R.sub.4 and n have the same
meaning as defined above).
This reaction is performed in pyridine. As concerns the amounts of
the reactants involved in this reaction, it is advantageous to use
the sulfurylamide in the amount of 1.0 to 4.0 equivalent weights of
Compound [XIII]. The reaction is generally performed under thermal
reflux and is completed in a period of 2 to 10 hours.
Finally, Compound [XIV] is converted into Compound [II-2] by
eliminating the group R.sub.4 by the usual methods, for example in
the same manner as that in the conversion of Compound [VIII] to
Compound [II-1].
Compound [II-3] is produced as shown below. First, a
4-oxo-piperidine derivative represented by the formula [XV]:
##STR100## (wherein, R.sub.2 and R.sub.4 have the same definitions
as defined above) is reacted with a compound represented by the
formula [XVI]: ##STR101## (wherein, R.sub.3 and n have the same
definitions as defined above) in an aromatic hydrocarbon type
solvent such as benzene, toluene and xylene in the presence of
sulfuric acid, an alkane-sulfonic acid (e.g. methanesulfonic acid)
or an aryl-sulfonic acid (e.g. p-toluenesulfonic acid) as a
catalyst to prepare a compound represented by formula [XVII]:
##STR102## (wherein, R.sub.2, R.sub.3, R.sub.4 and n have the same
definitions as defined above).
The reaction is advantageously performed by using p-toluenesulfonic
acid as a catalyst and removing the water through distillation
under reflux.
Compound [XVII] is then reduced with a complex metal hydride,
preferably lithium aluminum hydride, in an ether solvent such as
ethyl ether, dioxane and tetrahydrofuran to prepare a compound
represented by the formula [XVIII]: ##STR103## (wherein, R.sub.2,
R.sub.3, R.sub.4 and n have the same definitions as defined
above).
It is advantageous to use the complex methanol hydride in the
amount of 1.0 to 10, especially 2 to 6 equivalent weights of
Compound [XVII]. The reaction is preferably carried out from room
temperature to 150.degree. C., especially from 50.degree. to
120.degree. C. The reaction is usually completed in 2 to 24 hours
though it can be completed in shorter time according to the used
compounds.
Compound [XVIII] is reacted with sulfurylamide to prepare a
compound represented by the formula [XIX]: ##STR104## (wherein,
R.sub.2, R.sub.3, R.sub.4 and n have the same definitions as
defined above).
This reaction can be carried out in the same manner as that in the
preparation of Compound [XIV] from Compound [XIII].
Finally, Compound [XIX] is converted into Compound [II-3] by
eliminating the group R.sub.4 by the usual methods, for example in
the same manner as that in the conversion of Compound [VIII] to
Compound [II-1].
Isolation and purification of Compound [I] as well as the
above-mentioned intermediates are carried out according to
conventional methods in the field of organic synthetic chemistry,
for example, concentration, extraction, recrystallization and
chromatography. Specifically, since Compound [I] readily
crystallizes in general, it can be isolated and purified by
distilling off the solvent from the reaction mixture and
recrystallizing the residue from a suitable solvent such as
ethanol.
A pharmacologically acceptable acid addition salt of Compound [I]
may be obtained by reacting Compound [I] with a suitable acid in a
suitable solvent such as ethanol.
The pharmaceutical compositions of the present invention are
described below.
It is obvious from the foregoing various experimental data that
Compound [I] has a hypotensive activity.
In view of the hypotensive activity, the compounds of the present
invention may be used in various pharmaceutical forms for
administration. Pharmaceutical compositions of the present
invention are prepared by uniformly mixing an effective amount of
the compound in the form of a base or an acid addition salt as an
active ingredient with a pharmaceutically acceptable carrier.
According to the pharmaceutical forms suitable for administration,
the carrier may take various forms. It is desirable that the
pharmaceutical compositions are in single administration form
suitable for administration per os or by injection.
In preparation of the composition for oral administration, any
useful pharmaceutical carrier may be used. For example, water,
glycols, oils, alcohols, etc. may be used to prepare oral liquid
preparations such as suspensions and syrups, and excipients,
lubricants, binders, disintegrators, etc. may be used to prepare
powders, pills, capsules and tablets. Examples of the carriers are
glucose and lactose as the excipients, starch and sodium alginate
as the disintegrators, magnesium stearate, paraffin sulfate and
talc as the lubricants, and syrup, ethanol and gelatin as the
binders. The active ingredient is orally administered in a dose of
1-100 mg, particularly 10-60 mg, per day for an adult.
The preparation of Compound [I] and the present pharmaceutical
compositions are illustrated by the following examples, and the
preparation of the intermediates is illustrated by the following
reference examples.
EXAMPLE 1
1-(3,4-Dimethoxybenzoylmethyl)-4-(2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl)
-piperidine
In this example, 4.03 g of
4-(2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl)-piperidine
hydrochloride, 3.88 g of .omega.-bromo-3,4-dimethoxy-acetophenon,
4.2 ml of triethylamine and 30 ml of N,N-dimethylformamide are
mixed and stirred at room temperature for 2 hours and 30 minutes.
Subsequently, the reaction mixture is poured into 150 ml of ice
water and stirred therein for 3 hours. The crystals deposited are
separated by filtration and dried to obtain 5.36 g of a crude
product. The crude product is recrystallized from hot ethanol to
obtain 4.94 g of the desired product. Physical properties of the
product are shown in Tables 3-1, 3-2 and 3-3, and so are physical
properties of the compounds obtained in the following examples.
EXAMPLE 2
1-(3,4-Methylenedioxybenzoylmethyl)-4-(2-oxo-3,4-dihydro-2H-1,3-benzoxazin-
3-yl)-piperidine
In this example, 4.03 g of
4-(2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl)-piperidine
hydrochloride, 3.64 g of
.omega.-bromo-3,4-methylenedioxy-acetophenone, 4.2 ml of
triethylamine and 30 ml of N,N-dimethylformamide are mixed and
stirred at room temperature for 2 hours and 30 minutes.
Subsequently, the reaction mixture is poured into 150 ml of ice
water and stirred therein for 3 hours. The crystals deposited are
separated by filtration and dried to obtain 5.43 g of a crude
product. The crude product is recrystallized from hot ethanol to
obtain 4.82 g of the desired product.
EXAMPLE 3
1-[2-(3,4-Dimethoxyphenyl)-2-hydroxyethyl]-4-(2-oxo-3,4-dihydro-2H-1,3-benz
oxazin-3-yl)-piperidine
In this example, 3.0 g of
1-(3,4-dimethoxybenzoylmethyl)-4-(2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl
)-piperidine obtained in Example 1 is mixed with 150 ml of
methanol. While this mixture is stirred at 0.degree.-10.degree. C.,
0.8 g of sodium borohydride is added thereto over a period of 3
hours. The reaction solution is stirred overnight at room
temperature. Then, the solution is further mixed with 0.4 g of
sodium borohydride and stirred at room temperature for 3 hours. The
white crystals deposited are separated by filtration, washed with
methanol and water and dried to obtain 2.77 g of a crude product.
The crude product is recrystallized from ethanol to obtain 2.52 g
of the desired product.
EXAMPLE 4
1-[2-(3,4-Methylenedioxyphenyl)-2-hydroxyethyl]-4-(2-oxo-3,4-dihydro-2H-1,3
-benzoxazin-3-yl)-piperidine
In this example, 3.0 g of
1-(3,4-methylenedioxybenzoylmethyl)-4-(2-oxo-3,4-dihydro-2H-1,3-benzoxazin
-3-yl)-piperidine obtained in Example 2 is mixed with 150 ml of
methanol. While the mixture is stirred at 0.degree. to 10.degree.
C., 0.8 g of sodium borohydride is added thereto over a period of 3
hours. Then, the mixture is stirred overnight at room temperature.
The mixture is further mixed with 0.4 g of sodium borohydride and
stirred at room temperature for 3 hours. The white crystals
deposited are separated by filtration, washed with methanol and
water and dried to obtain 2.36 g of a crude product. In the
meantime, the filtrate is concentrated under reduced pressure. The
residue is mixed with water. The crystals deposited are separated
by filtration, washed with water and dried to obtain 0.37 g of a
crude product. The two crude products are combined and
recrystallized from ethanol to obtain 2.49 g of the desired
product.
EXAMPLE 5
1-[1
-(3,4-Dimethoxybenzoyl)-ethyl]-4-(2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl
)-piperidine
In this example, 4.03 g of
4-(2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl)-piperidine
hydrochloride, 4.10 g of .alpha.-bromo-3,4-dimethoxypropiophenone,
4.2 ml of triethylamine and 30 ml of N,N-dimethylformamide are
mixed and stirred at room temperature for 6 hours. Then, the
reaction mixture is poured into 150 ml of ice water. The oily
substance formed is separated by decantation of the water phase.
The oily substance is dissolved in 100 ml of ethyl acetate. The
solution is washed with a saturated aqueous sodium chloride, dried
and concentrated under reduced pressure to obtain 5.0 g of a crude
product. The crude product is recrystallized from ethanol to obtain
4.21 g of the desired product.
EXAMPLE 6
1-[3-(3,4-Dimethoxyphenyl)-3-hydroxypropan-2-yl]-4-(2-oxo-3,4-dihydro-2H-1,
3-benzoxazin-3-yl)-piperidine
In this example, 2.8 g of
1-[1-(3,4-dimethoxybenzoyl)-ethyl]-4-(2-oxo-3,4-dihydro-2H-1,3-benzoxazin-
3-yl)-piperidine obtained in Example 5 is mixed with 150 ml of
methanol. While the mixture is stirred at 0.degree. to 10.degree.
C., 2 g of sodium borohydride is added thereto over a period of one
hour. The mixture is further stirred for 3 hours at the same
temperature and then stirred overnight at room temperature. The
white crystals deposited are separated by filtration, washed with
methanol and water and dried to obtain 1.90 g of a crude product.
The crude product is recrystallized from ethanol to obtain 1.67 g
of the desired product.
EXAMPLE 7
1-(3,4,5-Trimethoxybenzoylmethyl)-4-(2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-
yl)-piperidine
In this example, 4.03 g of
4-(2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl)-piperidine
hydrochloride, 4.33 g of
.omega.-bromo-3,4,5-trimethoxy-acetophenone, 42 ml of triethylamine
and 100 ml of methanol are mixed and stirred at room temperature
for one hour and 40 minutes. The reaction solution is concentrated
under reduced pressure and the residue is mixed with water. The
crystals deposited are separated by filtration, washed with water
and dried to obtain 5.8 g of a crude product. The crude product is
recrystallized from ethanol to obtain 2.75 g of the desired
product.
EXAMPLE 8
1-[2-(3,4,5-Trimethoxyphenyl)-2-hydroxyethyl]-4-(2-oxo-3,4-dihydro-2H-1,3-b
enzoxazin-3-yl)-piperidine
In this example, 2.8 g of
1-(3,4,5-trimethoxybenzoylmethyl)-4-(2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3
-yl)-piperidine obtained in the same manner as in Example 7 is
mixed with 150 ml of methanol. While this mixture is stirred at
0.degree. to 10.degree. C., 1.5 g of sodium borohydride is added
thereto over a period of 2 hours. Then, the mixture is stirred
overnight at room temperature. The mixture is further mixed with 1
g of sodium borohydride and stirred overnight. The white crystals
deposited are separated by filtration, washed with methanol and
water and dried to obtain 1.96 g of a crude product. The crude
product is recrystallized from ethanol to obtain 1.76 g of the
desired product.
EXAMPLE 9
1-(3,4-Dimethoxybenzoylmethyl)-4-(3,4-dihydro-2,2-dioxo-1H-2,1,3-benzothiad
iazin-3-yl)-piperidine
In this example, 4.56 g of
4-(3,4-dihydro-2,2-dioxo-1H-2,1,3-benzothiadiazin-3-yl)-piperidine
hydrochloride, 3.88 g of 3,4-dimethoxy-.omega.-bromoacetophenone
and 3.04 g of triethylamine are dissolved in 100 ml of chloroform.
The solution is stirred at room temperature for 2 days. The
reaction mixture is washed with water, dried and concentrated under
reduced pressure. The residue is mixed with 10 ml of methanol and
allowed to stand for one hour. The crystals deposited are separated
by filtration, washed with methanol and dried to obtain 2.57 g of
crude crystals. The crude crystals are recrystallized from ethanol
to obtain 2.35 g of the desired product.
EXAMPLES 10-13
Compounds of Compound Nos. 11, 13, 14 and 17
Since the compounds designated as Compound Nos. 11, 13, 14 and 17
in Table 1 are obtained according to a similar procedure, the
procedure for the preparation of compound 13 is exemplified below.
Particulars on the other compounds are shown in Table 6.
In 30 ml of N,N-dimethylformamide, 4.545 g (15 m.mols) of
4-(3,4-dihydro-2,2-dioxo-1H-2,1,3-benzothiadiazin-1-yl)-piperidine
monohydrochloride, 3.884 g (15 m.mols) of
.omega.-bromo-3,4-dimethoxyacetophenone and 4.2 ml (30 m.mols) of
triethylamine are dissolved and the solution is stirred at room
temperature for 2 hours and 20 minutes. The reaction solution is
mixed with 300 ml of chloroform, washed with water (100 ml.times.2
and 50 ml.times.2), washed with a saturated aqueous sodium
chloride, dried and concentrated to dryness under reduced pressure.
Since the residue still contains N,N-dimethylformamide, it is
washed with 80 ml of water added thereto. The water layer is
removed by decantation. The residue is mixed with 50 ml of
methanol. The solvent is distilled off under reduced pressure. The
residual crystals are mixed with 3 ml of methanol and separated by
filtration to obtain 5.88 g of crude crystals. The crude crystals
are recrystallized from ethanol to obtain 5.55 g of
1-(3,4-dimethoxybenzoylmethyl)-4-(3,4-dihydro-2,2-dioxo-1H-2,1,3-benzothia
diazin-1-yl)-piperidine 3/2C.sub.2 H.sub.5 OH (Compound No.
13).
TABLE 6
__________________________________________________________________________
Solvent for recrys- Compound Reaction talliza- No. Starting
compound solvent Base tion Yield
__________________________________________________________________________
11 4-(3,4-Dihydro- .omega.-Bromo-3,4- DMF Triethylamine EtOH 69.5%
2,2-dioxo-1H- methylene- 20 ml 2.8 ml 2,1,3-benzothia- dioxy- (20 m
. mols) diazin-3-yl)- acetophenone piperidine 2.43 g hydrochloride
(10 m . mols) 3.04 g (10 m . mols) 13 4-(3,4-Dihydro-
.omega.-Bromo-3,4- DMF Triethylamine EtOH 83.2% 2,2-dioxo-1H-
dimethoxy- 30 ml 4.2 ml 2,1,3-benzothia- acetophenone (30 m . mols)
diazin-1-yl)- 3.884 g piperidine (15 m . mols) hydrochloride 5.454
g (15 m . mols) 14 Same as above .omega.-Bromo-3,4- DMF
Triethylamine EtOH 68.3% 4.545 g methylene- 30 ml 4.2 ml (15 m .
mols) dioxy- (30 m . mols) acetophenone 3.64 g (15 m . mols) 17
Same as above .alpha.-Bromo-3,4- DMF Triethylamine EtOH--H.sub.2 O
31.1% 4.17 g dimethoxy- 30 ml 3.82 ml (13.7 m . mols) propiophenon
(27.4 m . mols) 3.74 g (13.7 m . mols)
__________________________________________________________________________
(Note) The forms of the compounds are the same as those of Table
3.
EXAMPLES 14-18
Compounds of Compound Nos. 10, 12, 15, 16 and 18
Since the compounds designated as Compound Nos. 10, 12, 15, 16, and
18 in Table 1 are prepared according to a similar procedure, the
procedure for the preparation of Compound 10 is exemplified below.
Particulars on the other compounds are shown in Table 7.
In 150 ml of methanol, 2.2 g of
1-(3,4-dimethoxybenzoylmethyl)-4-(3,4-dihydro-2,2-dioxo-1H-2,1,3-benzothia
diazin-3-yl)-piperidine is suspended. While this suspension is
stirred at room temperature, 1.0 g of sodium borohydride is added
thereto by portions over a period of four hours. The mixture is
stirred overnight at room temperature and 400 mg of sodium
borohydride is added thereto. Then, the mixture is stirred
overnight. The reaction solution is concentrated under reduced
pressure. The residue is mixed with 100 ml of water and adjusted to
pH 9.3 with concentrated hydrochloric acid. The resultant mixture
is extracted with chloroform. The organic layer is washed with
water, dried and freed from the solvent by distillation to obtain a
syrup as a residue. This residue is crystallized by adding methanol
thereto. The crystals are separated by filtration to obtain 1.93 g
of crude crystals. The crude crystals are recrystallized from
ethanol to obtain 1.45 g of
1-[2-(3,4-dimethoxyphenyl)-2-hydroxyethyl]-4-(3,4-dihydro-2,2-dioxo-1H-2,1
,3-benzothiadiazin- 3-yl)-piperidine (Compound No. 10).
TABLE 7
__________________________________________________________________________
Re- Solvent Com- duc- for re- pound Reaction ing crystal- No.
Starting compound solvent agent lization Yield
__________________________________________________________________________
12 1-(3,4-Methylenedioxybenzoylmethyl)-4-(3,4- MeOH NaBH.sub.4 EtOH
65.6% dihydro-2,2-dioxo-1H-2,1,3-benzothiadiazin- 150 ml 1.4 g
3-yl)-piperidine 2.2 g 15 1-(3,4-Dimethoxybenzoylmethyl)-4-(3,4-
MeOH NaBH.sub.4 EtOH 82.3%
dihydro-2,2-dioxo-1H-2,1,3-benzothiadiazin- 150 ml 1.5 g
1-yl)-piperidine 3.0 g 16
1-(3,4-Methylenedioxybenzoylmethyl)-4-(3,4- MeOH NaBH.sub.4 EtOH
67.3% dihydro-2,2-dioxo-1H-2,1,3-benzothiadiazin- 150 g 1.5 g
1-yl)-piperidine 3.0 g 18 1-[1-(3,4-Dimethoxybenzoyl)-ethyl]-4-
MeOH NaBH.sub.4 EtOH/H.sub.2 O 57.9%
(3,4-dihydro-2,2-dioxo-1H-2,1,3- 100 ml 2.0 g
benzothiadiazin-1-yl)-piperidine monohydrochloride 1.7 g
__________________________________________________________________________
(Note) The forms of the compounds are the same as those of Table
3.
EXAMPLE 19
(Example of preparing 10,000 5 mg-tablets)
Compound 4: 50 g
Magnesium stearate: 4 g
Crystalline cellulose: 746 g
The above-described ingredients are mixed for 5 minutes by means of
a mixer. The resulting mixed powder is made into 10,000 tablets of
6.0 mm in diameter, 2.5 mm in thickness, and 80 mg in weight using
a tablet-making machine (Model HU-37; made by Kikusui Seisakusho)
equipped with a pestle having a plane surface and round
corners.
EXAMPLE 20
(Example of preparing a powder)
Compound 14: 110 g
Lactose: 890 g
The above-described ingredients are mixed for 10 minutes using a
mixer to obtain a uniform mixture (powder).
REFERENCE EXAMPLE 1
1-Benzyl-4-[N-(o-hydroxybenzyl)-amino]-piperidine ##STR105##
In this reference example, 9.76 g of salicylaldehyde, 15.12 g of
1-benzyl-4-amino-piperidine and 100 ml of methanol are mixed and
stirred at room temperature for one hour. While the resultant
mixture is cooled with ice, 3.2 g of sodium borohydride is added
thereto over a period of one hour and 30 minutes. Then, the mixture
is stirred at room temperature for 2 hours. The resultant reaction
mixture is poured into 1 l of ice water. The light yellow crystals
deposited are separated by filtration and then dissolved in 200 ml
of ethyl acetate. The ethyl acetate solution is washed with a
saturated aqueous sodium chloride, dried and subsequently
concentrated under reduced pressure to obtain 19.0 g of light
yellow crystals. The crystals are recrystallized from ethanol to
obtain 12.0 g of the desired product.
Melting point: 92.5.degree.-93.0.degree. C.
Elementary analysis (%): C.sub.19 H.sub.24 N.sub.2 O:
______________________________________ C H N
______________________________________ Calculated 76.99 8.16 9.45
Found 76.97 8.10 9.37 ______________________________________
REFERENCE EXAMPLE 2
1-Benzyl-4-(2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl)-piperidine
##STR106##
In this reference example, 17.7 g of
1-benzyl-4-[N-(o-hydroxybenzyl)-amino]-piperidine obtained by the
procedure of Reference Example 1, 19.4 g of 1,1'-carbonyldimidazole
and 150 ml of tetrahydrofuran are mixed, stirred for 2 hours and 30
minutes, refluxed and then concentrated under reduced pressure.
Subsequently, the formed crystalline residue is mixed with water
and separated by filtration to obtain 18.0 g of crude crystals. The
crude crystals are recrystallized from a mixture of n-hexane and
ethyl acetate [50:7 (V/V)] to obtain 14.85 g of the desired
product.
Melting point: 106.0.degree.-107.0.degree. C.
Elementary analysis (%): C.sub.20 H.sub.22 N.sub.2 O.sub.2 :
______________________________________ C H N
______________________________________ Calculated 74.51 6.88 8.69
Found 74.80 6.98 8.74 ______________________________________
REFERENCE EXAMPLE 3
4-(2-Oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl)-piperidine
hydrochloride ##STR107##
In this reference example, 16.0 g of
1-benzyl-4-(2-oxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl)-piperidine
and 4.0 g of 10% palladium carbon are added to a mixture of 150 ml
of water, 50 ml of 1 N hydrochloric acid and 300 ml of methanol.
While the resultant mixture is stirred, hydrogen gas is passed
therethrough overnight. Then, the reaction mixture is filtered and
the filtrate is concentrated. The white crystals as a residue are
mixed with methanol and separated by filtration to obtain 11.4 g of
the desired product.
Melting point: 288.0.degree.-290.0.degree. C.
Elementary analysis (%): C.sub.13 H.sub.17 N.sub.2 O.sub.2 Cl:
______________________________________ C H N
______________________________________ Calculated 58.10 6.38 10.42
Found 57.92 6.40 10.26 ______________________________________
REFERENCE EXAMPLE 4
1-Benzyl-4-[N-(o-nitrobenzyl)-amino]-piperidine dihydrochloride
##STR108##
In this reference example, 5.24 g of 1-benzyl-4-amino-piperidine
dihydrochloride, 3.02 g of o-nitrobenzaldehyde, 2.02 g of
triethylamine and 30 ml of methanol are mixed and stirred at room
temperature for one hour. The resultant solution is cooled with ice
and stirred. To the stirred solution, 1 g of sodium borohydride is
added little by little over a period of one hour. Then, the mixture
is brought back to room temperature and stirred at room temperature
for 2 hours. The resultant solution is poured into 200 ml of ice
water and extracted with ether. The organic layer is washed with
water, dried and concentrated. The oily residue is dissolved in 20
ml of ethanol. The solution is mixed with 10 ml of a solution of
5.7 N hydrochloric acid in ethyl acetate. The white crystals
deposited are separated by filtration, washed with 20 ml of ethyl
acetate and dried to obtain 5.70 g of a crude product. The crude
product is recrystallized from hot ethanol to obtain 2.90 g of the
desired product.
Melting point: 260.0.degree.-263.5.degree. C.
Elementary analysis (%): C.sub.19 H.sub.25 N.sub.3 O.sub.2 Cl.sub.2
:
______________________________________ C H N
______________________________________ Calculated 57.29 6.33 10.55
Found 57.19 6.48 10.27 ______________________________________
REFERENCE EXAMPLE 5
1-Benzyl-4-[N-(o-aminobenzyl)-amino]-piperidine trihydrochloride
##STR109##
In this reference example, 31.8 g of
1-benzyl-4-[N-(o-nitrobenzyl)-amino]-piperidine dihydrochloride,
3.2 g of 10% Pd-C and 500 ml of water are mixed and stirred at room
temperature. Then, about 6 l of hydrogen gas is absorbed by the
mixture. Then the reaction is discontinued and the Pd-C is removed
by filtration. The aqueous solution is adjusted to pH 11 with an
aqueous sodium hydroxide and then extracted with ethyl acetate. The
organic layer is washed with water, dried and concentrated. The
resulting oily product is dissolved in 140 ml of ethanol. Then, 70
ml of a solution of 5.7 N hydrochloric acid in ethyl acetate is
added thereto. The white crystals deposited are separated by
filtration, washed with ethyl acetate and dried to obtain 23.5 g of
a crude product. The crude product is recrystallized from a mixed
solvent of methanol and ethyl acetate to obtain 15.0 g of the
desired product.
Melting point: 225.0.degree.-228.0.degree. C.
Elementary analysis (%): C.sub.19 H.sub.28 N.sub.3 Cl.sub.3 :
______________________________________ C H N
______________________________________ Calculated 56.37 6.97 10.38
Found 56.35 7.00 10.31 ______________________________________
REFERENCE EXAMPLE 6
1-Benzyl-4-(3,4-dihydro-2,2-dioxo-1H-2,1,3-benzothiadiazin-3-yl)-piperidine
##STR110##
In this reference example, 1.10 g of
1-benzyl-4-[N-(o-aminobenzyl)-amino]-piperidine trihydrochloride is
mixed with 5 ml of water. Then, 15 ml of 1 N aqueous sodium
hydroxide is added to the solution with cooling. The mixture is
extracted with 20 ml of chloroform four times. The chloroform layer
is washed with 20 ml of water two times. The resultant layer is
dried and concentrated under reduced pressure to obtain 670 mg of
1-benzyl-4-[N-(o-aminobenzyl)amino]-piperidine as an oily
residue.
Then, 590 mg of 1-benzyl-4-[N-(o-aminobenzyl)amino]-piperidine, 600
mg of sulfurylamide and 12 ml of pyridine are mixed and refluxed
with heating for 2 hours. The reaction mixture is cooled to room
temperature and poured into 50 ml of ice water. The white crystals
deposited are separated by filtration, washed with 10 ml of water
and dried to obtain 520 mg of the desired product as crystals.
NMR (.delta. ppm in CDCl.sub.3): 1.37-2.27(6H, m), 2.66-3.10 (2H,
m), 3.42(2H, s), 3.83(1H, m), 4.62(2H, s), 5.76(1H, s)
(exchangeable proton), 6.33-7.46(9H, m).
IR (KBr) .nu..sub.max.sup.cm.spsp.-1 : 1340, 1165 (SO.sub.2)
cm.sup.-1.
REFERENCE EXAMPLE 7
4-(3,4-Dihydro-2,2-dioxo-1H-2,1,3-benzothiadiazin-3-yl)-piperidine
##STR111##
In this reference example, 7.14 g (20 m.mols) of
1-benzyl-4-(3,4-dihydro-2,2-dioxo-1H-2,1,3-benzothiadiazin-3-yl)-piperidin
e, 2 g of 10% palladium carbon, 20 ml of 1 N hydrochloric acid, 60
ml of water and 120 ml of methanol are mixed. While the mixture is
stirred at 40.degree. C., hydrogen gas is blown into the mixture at
40.degree. C. for 20 hours. The reaction mixture is filtered to
remove palladium carbon. The filtrate is concentrated to dryness to
obtain 5.0 g of the desired product.
NMR (.delta. ppm in d.sub.6 DMSO): 1.47-2.20(4H, m), 2.60-4.35 (5H,
m), 4.63(2H, s), 6.60-7.40(4H, m), 9.10(2H, broad s) (exchangeable
proton), 10.46 (1H, s) (exchangeable proton).
IR (KBr) .nu..sub.max.sup.cm.spsp.-1 : 1330, 1155 (SO.sub.2)
cm.sup.-1.
REFERENCE EXAMPLE 8
1-Benzyl-4-[N-(o-aminomethylphenyl)-amino]piperidine ##STR112##
In this reference example, the mixture of 13.6 g of anthranilamide,
18.9 g of 1-benzyl-4-piperidone, 1.0 g of p-toluene-sulfonic acid
monohydrate and 200 ml of benzene is refluxed in a Dean Stark
apparatus for 6 hours to distil off water. The resultant suspension
of the Schiff-base is concentrated. The residue is mixed with 250
ml of dry dioxane to form a suspension. Separately, 100 ml of dry
dioxane and 12.4 g of lithium aluminum hydride are mixed. The above
Schiff-base suspension is added little by little to the mixture
with stirring without cooling. The mixture is stirred for one hour
and then refluxed with heating for 18 hours. The reaction solution
is cooled to room temperature and poured little by little into 1.3
l of ice water. The resultant suspension is poured little by little
into a funnel previously coated with a filter aid and subjected to
suction filtration. The cake on the funnel is washed with 500 ml of
chloroform and filtered. The organic layer is washed with water,
dried and concentrated to obtain 22.9 g of a crude product. The
crude product is recrystallized from hot ethanol to obtain 18.7 g
of the desired product.
Melting point: 117.0.degree.-118.0.degree. C.
Elementary analysis (%): C.sub.19 H.sub.25 N.sub.3 :
______________________________________ C H N
______________________________________ Calculated 77.25 8.53 14.22
Found 77.45 8.66 13.98 ______________________________________
REFERENCE EXAMPLE 9
1-Benzyl-4-(3,4-dihydro-2,2-dioxo-2,1,3-benzothiadiazin-1-yl)-piperidine
monohydrochloride ##STR113##
In this reference example, 33.0 g (112.4 m.mols) of
1-benzyl-4-[N-(o-aminomethylphenyl)-amino]-piperidine, 21.6 g
(224.8 m.mols) of sulfuryl amide and 250 ml of pyridine are mixed
and refluxed with heating for 8 hours. The reaction solution is
cooled to room temperature, concentrated to 70 ml and poured into
500 ml of ice water. The mixture is mixed with 300 ml of
chloroform, stirred and adjusted to pH 9 with 2 N aqueous sodium
hydroxide. The chloroform layer is separated with separating funnel
and the remaining water layer is further extracted with chloroform
(300 ml.times.3). The chloroform layers are combined, washed with
water (300 ml.times.4), dried and concentrated to obtain an oily
residue. This residue is dissolved in 150 ml of ethanol. To the
solution, 50 ml of 5.7 N hydrogen chloride in ethyl acetate is
added. The resultant solution is concentrated under reduced
pressure. The crystalline residue is mixed with 50 ml of ethanol
and filtered to obtain 29.0 g of the desired product. This compound
is tested for NMR after it has been freed from hydrochloric acid,
and it is tested for IR in its unaltered form of hydrochloride.
NMR (.delta. in ppm in CDCl.sub.3): 1.66-2.33(6H, m), 2.6-3.2(2H,
m), 3.48(2H, s), 4.0(1H, m), 4.43(2H, s), 4.80(1H, br.s)
(exchangeable proton), 7.0-7.4(9H, m).
IR (KBr) .nu..sub.max.sup.cm.spsp.-1 : 1330, 1165 (SO.sub.2)
cm.sup.-1.
REFERENCE EXAMPLE 10
4-(3,4-Dihydro-2,2-dioxo-2,1,3-benzothiadiazin-1-yl)-piperidine
monohydrochloride ##STR114##
While a mixture of 16 g of
1-benzyl-4-(3,4-dihydro-2,2-dioxo-2,1,3-benzothiadiazin-1-yl)-piperidine
monohydrochloride, 4 g of 10% palladium carbon, 160 ml of water and
240 ml of methanol is stirred at 40.degree. C., hydrogen gas is
blown into the mixture for 20 hours. Then, the resultant reaction
mixture is freed from palladium carbon by filtration. The filtrate
is concentrated to dryness to obtain 11.2 g of crude crystals of
the desired product. This compound is tested for NMR after it has
been freed from hydrochloric acid, and it is tested for IR in its
unaltered form of hydrochloride.
NMR (.delta. ppm in CDCl.sub.3): 1.60-3.26(8H, m), 3.70-4.26 (3H,
m) (exchangeable proton 2H), 4.40(2H, s), 6.86-7.46(4H, m).
IR (KBr) .nu..sub.max.sup.cm.spsp.-1 : 1340, 1160 (SO.sub.2)
cm.sup.-1.
* * * * *